Central nervous system (CNS)-infiltrating lymphocytes contribute to the progression of cerebral infarction in ischemic stroke. The damaged brain, in turn, exerts suppressive effects on the immune system. The temporal relationship of this reciprocal interaction between immune system and ischemic brain has not been defined, making immune intervention to limit brain damage exceedingly difficult. Moreover, the high prevalence of infection in stroke patients requires a better understanding of how stroke influences immune responses systemically and within the brain, to combat immune-related post-stroke complications. We recently showed that natural killer (NK) cells - a critical component of the innate immune system - are abundantly represented in peri-infarcted area of brain sections from autopsies of stroke patients. In a mouse model of cerebral ischemia, we showed that ischemic neuron-derived fractalkine recruited NK cells, which could accelerate brain infarction in the acute stage of ischemic stroke. Subsequently, NK cells exhibited decreased frequency and compromised function. Those NK cells expressed neurotransmitter receptors, and their exposure to acetylcholine impaired function. Based on these findings, we hypothesize that the physical proximity of ischemic neurons and NK cells in the CNS, as well as different neuronal signals received by NK cells within the CNS and the peripheral lymphoid organs, underlie the differential mechanisms responsible for NK cell deficiency in the periphery and in the brain. This would lead to NK cell-associated immune deficiency that favors the development of infection and post-stroke complications. To test this hypothesis, we will analyze the pathways that lead to NK cell deficiency in stroke, and relate those findings to clinical outcomes. The specific aims are: 1) To define the temporal events associated with functional changes in NK cells from competency to deficiency, and to identify the characteristics acquired by NK cells in the periphery and in the CNS after brain ischemia; 2) To identify the mechanisms responsible for NK cell deficiency in the periphery and in the CNS after brain ischemia; 3) To investigate the clinical relevance of NK cell deficiency on infection in stroke, and to test strategies of manipulation of NK cell deficiency for the reduction of post-stroke infection. In all, this proposa will advance the understanding of key neuroimmune interactions that might allow design of strategies of NK cell-based intervention as a new tool limiting risks of post-stroke infection.